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REVIEW ARTICLE
CME
Antiplatelet Drugs: A Review of Their Pharmacology
and Management in the Perioperative Period
Richard Hall, MD, FRCPC, FCCP,* and C. David Mazer, MD, FRCPC†‡
In the normal course of the delivery of care, anesthesiologists encounter many patients who
are receiving drugs that affect platelet function as a fundamental part of primary and
secondary management of atherosclerotic thrombotic disease. There are several antiplatelet
drugs available for use in clinical practice and several under investigation. Aspirin and
clopidogrel (alone and in combination) have been the most studied and have the most
favorable risk-benefit profiles of drugs currently available. Prasugrel was recently approved
for patients with acute coronary syndrome undergoing percutaneous interventions. Other
drugs such as dipyridamole and cilostazol have not been as extensively investigated. There are
several newer investigational drugs such as cangrelor and ticagrelor, but whether they confer
significant additional benefits remains to be established. Management of patients who are
receiving antiplatelet drugs during the perioperative period requires an understanding of the
underlying pathology and rationale for their administration, pharmacology and pharmacokinetics, and drug interactions. Furthermore, the risk and benefit assessment of discontinuing or
continuing these drugs should be made bearing in mind the proposed surgery and its inherent
risk for bleeding complications as well as decisions relating to appropriate use of general or
some form of regional anesthesia. In general, the safest approach to prevent thrombosis seems
to be continuation of these drugs throughout the perioperative period except where concerns
about perioperative bleeding outweigh those associated with the development of thrombotic
occlusion. Knowledge of the pharmacodynamics and pharmacokinetics of antiplatelet drugs
may allow practitioners to anticipate difficulties associated with drug withdrawal and
administration in the perioperative period including the potential for drug interactions.
(Anesth Analg 2011;112:292–318)
A
nesthesiologists frequently encounter patients with
atherothrombotic disease who are receiving drugs
deliberately designed to impair the normal function of the coagulation system. The platelet is integral to the
initiation of thrombosis.1 Drugs that affect platelet function
are a fundamental part of primary and secondary management of atherosclerotic thrombotic disease.2 As reviewed in
various guideline documents,3 authoritative reviews, and
meta-analyses, the indications for the use of antiplatelet
drugs in the management of thrombotic diseases include
stroke,4 – 6 acute myocardial infarction (AMI),7–9 acute
coronary syndrome (ACS),10,11 angina,12 percutaneous
coronary intervention (PCI),13–15 cardiac surgery,16 –20
primary21–23 and secondary cardiovascular disease prevention,7,14,23–26 peripheral vascular disease,27–31 and thrombotic disorders such as atrial fibrillation.7,32 There are
several antiplatelet drugs available for use in clinical practice and several under investigation (Fig. 1).33 Management
of patients who are receiving antiplatelet drugs during the
From the *Departments of Anesthesia, Medicine, Surgery, and Pharmacology, Dalhousie University/Queen Elizabeth II Health Sciences Centre,
Halifax, Nova Scotia; †Keenan Research Center/Li Ka Shing Knowledge
Translation Institute, Saint Michael’s Hospital, Toronto; and ‡Departments
of Anesthesia and Physiology, University of Toronto, Toronto, Ontario,
Canada.
Accepted for publication October 1, 2010.
Conflict of Interest: See Disclosures at the end of the article.
Address correspondence and reprint requests to C. David Mazer, MD,
FRCPC, Department of Anesthesia, St. Michael’s Hospital, 30 Bond St.,
Toronto, ON M5B 1W8, Canada. Address e-mail to [email protected].
Copyright © 2011 International Anesthesia Research Society
DOI: 10.1213/ANE.0b013e318203f38d
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perioperative period requires an understanding of the
underlying pathology and rationale for their administration, pharmacology and pharmacokinetics, and drug interactions. The risk versus benefit assessment of continuing or
discontinuing these drugs should be made bearing in mind
the proposed surgery and its inherent risk for bleeding or
thrombotic complications as well as decisions relating to
appropriate use of general or some form of regional anesthesia. Reports of late coronary and carotid artery stent
occlusion, particularly in the perioperative period after
discontinuation of an antiplatelet drug,34 have served to
heighten concern about the perioperative management of
these drugs. This review focuses on the perioperative use of
some of the current and investigational drugs affecting
platelet function (Table 1) by describing their pharmacology
including pharmacokinetics, pharmacodynamics, and drug
interactions of particular relevance, management in the perioperative period in light of the above reports, and areas where
further research should occur. Where possible, suggestions
are made about the perioperative management of these drugs
for patients receiving general or regional anesthesia.
ANTIPLATELET DRUGS
Aspirin
Aspirin has a central role in the prevention of thromboembolic complications from atherosclerotic disease and is the
leading therapeutic drug for this purpose.3,35
Pharmacokinetics
After oral administration, aspirin is rapidly absorbed from the
upper gastrointestinal (GI) tract with peak levels occurring
February 2011 • Volume 112 • Number 2
Antiplatelet Drugs in the Perioperative Period
Figure 1. Agonists to platelet activation and antiplatelet drugs. COX ⫽ cyclooxygenase; NSAIDs ⫽ nonsteroidal antiinflammatory drugs;
LMWH ⫽ low-molecular-weight heparin; TxA2 ⫽ thromboxane A2; PAR-1 ⫽ protease-activated receptor 1; cAMP ⫽ cyclic adenosine
monophosphate; cGMP ⫽ cyclic guanosine monophosphate; ADP ⫽ adenosine diphosphate; VASP ⫽ vasodilator stimulated phosphoprotein;
5HT ⫽ 5 hydroxytryptamine; vWF ⫽ von Willebrand factor; 5⬘AMP ⫽ 5⬘ adenosine monophosphate; PAF ⫽ platelet aggregating factor; GP ⫽
glycoprotein; P ⫽ purinergic. (From Gladding et al.,33 with permission.)
approximately 30 to 40 minutes after ingestion.36 For the
majority of patients, there does not seem to be any additional effect on platelet activity at doses ⬎300 mg.37 Use of
enteric-coated formulations may considerably delay the
time to peak effect.38
Pharmacodynamics
The effect of aspirin on platelet function is to permanently
inactivate a key platelet enzyme (cyclooxygenase [COX]).39
This effect can only be reversed by generation of new
platelets40 thus permitting once-daily dosing. Conditions
for which aspirin is indicated and its lowest effective dose
are given in Table 2.35
COX exists in 2 isoforms (COX-1 and COX-241) and
catalyzes the first step in prostanoid synthesis, the conversion
of arachidonic acid to prostaglandin (PG)H2. PGH2 is rapidly
converted to several bioactive prostanoids including thromboxane A2 (TXA2) and PGI2.41 Aspirin inhibits COX by
diffusing into the COX channel within the membrane to the
catalytic site for the enzyme (an arginine 120 residue, which is
a common binding site for all COX inhibitors) and then
acetylating a serine residue (serine 529 in human COX-1 and
serine 516 in human COX-2). This prevents arachidonic acid
from gaining access to the catalytic site of the enzyme.42
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In response to various stimuli, platelets generate TXA2,
a process that is very sensitive to inhibition by aspirin43 and
largely mediated by COX-1. In contrast, the endothelium
generates PGI2, a process that is much less sensitive to
inhibition by aspirin and largely mediated by COX-2.35 As
a consequence, low-dose aspirin has limited measurable
effects on PGI2-dependent vascular functions including
arterial blood pressure regulation,44 renal function,45 or
interference with the antihypertensive effects of diuretics
and angiotensin-converting enzyme (ACE) inhibitors.46 A
daily dose of 30 mg aspirin is sufficient to completely
suppress TXA2 production within 1 week.43
Adverse Effects
The major adverse effect of aspirin administration is an
increased risk of bleeding complications,35,47 albeit with a
very favorable risk-benefit ratio.47 One of the most common
sites for bleeding is the GI tract,48 although this risk may be
ameliorated by the use of gastroprotective drugs such as
proton pump inhibitors (PPIs).49
Drug Interactions
The concomitant administration of nonselective reversible
COX-1 inhibitors such as ibuprofen and naproxen may lead
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REVIEW ARTICLE
Table 1. Properties of Current Oral and Investigational Antiplatelet Drugs
Time required to
recover adequate
Metabolism
Permanent platelet function
to active
after drug
platelet
metabolite
Mechanism of
Route of
administration
Route of elimination inactivation
Drug
Class
action
administration required
Aspirin
Salicylate
Cyclooxygenase
Oral
No
Liver, by deacetylation
Yes
30% at 48 h
enzyme
to salicylic acid
inhibition
Clopidogrel
Thienopyridine
P2Y12 receptor
Oral
Yes
Liver, by a 2-step
Yes
40% at 3 d
blockade
process involving
CYP3A5/2CD19 to
active metabolite
Oral
Yes
Liver, by CYP2CD19 to
Yes
4–8 d
Ticlopidine
Thienopyridine
P2Y12 receptor
blockade
active metabolite
Oral
Yes
Liver, by CYP3A4 to
Yes
2–3 d
Prasugrel
Thienopyridine
P2Y12 receptor
blockade
active metabolite
Oral, IV
No
Liver and kidney with
No
8 h after a single
Elinogrel
Sulfonylurea
P2Y12 receptor
blockade
minimal metabolism
10-mg dose;
longer with
higher doses
IV
No
Dephosphorylation
No
Rapid (min–h)
Cangrelor
ADP analog
P2Y12 receptor
blockade
Oral
No
Liver, active metabolite
No
57% at 24 h
Ticagrelor
Cyclopentyltriazolopyrimidine P2Y12 receptor
blockade
Dipyridamole Phosphodiesterase inhibitor PDE inhibition
Oral
No
Liver, enterohepatic
No
2 d (?)
recirculation
Cilostazol
Phosphodiesterase III
PDE III
Oral
No
Liver, CYP3A4/2CD19
No
2 d (?)
inhibitor
inhibition
active metabolite
Terutroban
PAR-1 receptor blocking
PAR-1 blockade
Oral
No
?
?
?
drug
E5555
PAR-1 receptor blocking
PAR-1 blockade
Oral
No
?
No
?
drug
SCH-530348 PAR-1 receptor blocking
PAR-1 blockade
Oral
No
Liver, biliary excretion
No
?
drug
ADP ⫽ adenosine diphosphate; PDE ⫽ phosphodiesterase; PAR-1 ⫽ protease-activated receptor 1.
Table 2. Disorders for Which Aspirin Has Been
Shown to Be Effective and the Lowest Effective
Daily Dose
Disorder
Hypertension
Chronic stable angina
Polycythemia vera
Unstable angina
Acute myocardial infarction
Transient ischemic attack and ischemic stroke
Severe carotid artery stenosis
Acute ischemic stroke
Atrial fibrillation
Men at high cardiovascular risk
Immediate postcardiac surgery graft preservation
Lowest effective
daily dose (mg)
75
75
100
75
160
50
75
160
325
75
?325
Adapted from Patrono et al.,35 with permission.
to impairment in the efficacy of aspirin.42,50 –53 There is
competition between the nonselective COX inhibitors and
aspirin for the common docking site within the COX-1
channel (arginine 120), which may prevent aspirin from
acetylating the serine residue at position 529.42 Such an
interaction could occur in the perioperative period when
these drugs are often coadministered. Retrospective cohort
studies have not demonstrated any increased risk of myocardial infarction (MI) when ketorolac was administered
postoperatively with antiplatelet drugs.54 The coadministration of aspirin and COX-1 inhibitors after cardiac surgery has not been well studied. Given the potential for COX
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inhibitors (particularly COX-2 inhibitors55) to exacerbate
ischemic heart disease56 –58 (including after cardiac surgery59), it is suggested that, until further research is done,
where possible, analgesic drugs with minimal effects on
COX (e.g., acetaminophen42,56) be considered particularly
in patients who have undergone a PCI procedure with stent
placement.
Aspirin “Resistance” and “High on Treatment Platelet
Reactivity (HPR)”
No antithrombotic drug currently available is 100% effective in the prevention of adverse thrombotic events.60 The
incidence of true aspirin “resistance,” defined as the inability of aspirin to inhibit COX-1– dependent TXA2 production, is very low (approximately 1%–2%).61 Current
estimates suggest that up to 30% of treated individuals
may, however, have an inadequate response to aspirin
treatment at doses ⬍300 mg daily,62 and are susceptible
to treatment failure. Treatment failure may be associated
with significant adverse outcomes including death, MI,
cerebrovascular accident, closure of saphenous vein
grafts, and occlusion of peripheral arterial grafts.63 The
reasons for inadequate drug effect while on treatment
have been investigated. Patient noncompliance with the
prescribed medication may be a significant cause
(3%– 40%).64 Indeed, studies reporting the incidence of
treatment failure that have not controlled for noncompliance should be considered flawed methodologically.
ANESTHESIA & ANALGESIA
Antiplatelet Drugs in the Perioperative Period
Figure 2. Mechanism of action and laboratory evaluation of clopidogrel and aspirin responsiveness. AA ⫽ arachidonic acid; ADP ⫽ adenosine
diphosphate; COX-1 ⫽ cyclooxygenase-1; CLP ⫽ clopidogrel; LTA ⫽ light transmittance aggregometry; PRP ⫽ platelet-rich plasma; PAC-1 ⫽
activated glycoprotein IIb/IIIa receptor; PFA-100 ⫽ platelet function analyzer-100; PLC␤ ⫽ phospholipase␤; ASA ⫽ aspirin; TP ⫽ thromboxane
receptor; TxB2 ⫽ thromboxane B2; TEG® ⫽ thrombelastography; VASP-P ⫽ vasodilator stimulated phosphoprotein–phosphorylated. (From
Gurbel and Tantry,317 with permission.)
Moreover, failure to take antiplatelet drugs as prescribed
may place patients at increased risk for thrombotic
complications because of rebound platelet activation.65
However, a number of patients have been observed to
have inadequate response to aspirin treatment despite
receiving doses considered adequate for the majority of
patients. These patients are discovered by using an in
vitro test of platelet function (Fig. 2) (with assay limits
defined for the test by the investigator) and are described
as having “high platelet reactivity (HPR)” or “biochemical resistance.”66 HPR is an ex vivo diagnosis based on
testing and should be considered as a primary event.
Clinical thrombosis is a very late sign of HPR if it is
present, but is not definitive proof that HPR is the cause
of thrombosis. Differences in thrombotic outcomes for
patients whose antiplatelet dosing was based on ex vivo
platelet function test results have been demonstrated.63,67,68 HPR is measured differently using different tests and different values based on the drug being
evaluated and the investigator definition.
Conditions associated with an inflammatory response
such as unstable angina,69 AMI,70 diabetes,71 and cardiac
surgery72 are associated with HPR in aspirin-treated
patients. In animals, the development of atherosclerosis
is accompanied by an inflammatory response mediated
February 2011 • Volume 112 • Number 2
through the thromboxane pathway with generation of
free radicals.73 A link between direct measures of inflammation and increased thrombogenicity has recently been
demonstrated.74 Generation of inflammatory cytokines
as part of the inflammatory response leads to endothelial
and monocyte cell activation with expression of tissue
factor, a potent stimulus for platelet activation.75,76 In
turn, activated platelets contribute to further inflammation by releasing other inflammatory mediators such as
platelet activating factor.77 Surgery leads to increases in
catecholamines.72,78 Catecholamines have been demonstrated to enhance the inflammatory response in vitro79
and in an animal model,80 and to increase platelet
reactivity,81,82 which is only partially responsive to inhibition by aspirin.83
Other possible mechanisms for HPR include genetic
polymorphisms of the platelet glycoprotein receptor84 and
COX-1 and COX-2 alleles,85 generation of aspirininsensitive COX,69 and increased platelet turnover.86 In
combination, these factors may lead to reduced aspirin
effect20,86 and increased risk for perioperative ischemic
events.87 In the perioperative period, although the effectiveness of aspirin to prevent thrombotic complications has
been demonstrated,16 its efficacy may be reduced in a
substantial proportion of patients.88
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Table 3. Possible Causes of Nonresponse to Aspirin or Clopidogrel
Specific for aspirin
Reduced bioavailability
Drug interaction: NSAIDs
Common to both aspirin and clopidogrel
Nonatherothrombotic causes of vascular event
(e.g., arteritis, cardiac embolism)
Baseline individual variability
● 1Baseline platelet reactivity
● 1BMI
● Diabetes/insulin resistance
Reduced bioavailability
● Failure to prescribe
● Poor compliance/inadequate intake
● Underdosing
● Variable absorption/metabolism
Increased platelet turnover
● 1Platelet production (perioperative stress)
● Exogenous administration (transfusion)
● 1Platelet reactivity
Genetic polymorphisms
Platelet GP Ia/IIa Ib/V/IX, and IIb/IIIa receptors
● Collagen, vWF
● COX-1, -2
● Thromboxane A2
● Factor XIII Val34Leu (2factor XIII activation)
Alternate pathways of platelet activation
● Activation by other pathways (e.g.,
catecholamines)
● 1COX from nucleated cells
● non-COX-thromboxane A2 synthesis
Tachyphylaxis
Specific for clopidogrel
Reduced bioavailability
Drug interaction: drugs metabolized by
the cytochrome P-450 CYP3A4 system
Genetic polymorphisms
● P2Y12 H2 haplotype
● CYP3A4
● CYP2C19
NSAIDs ⫽ nonsteroidal antiinflammatory drugs; COX ⫽ cyclooxygenase; vWF ⫽ von Willebrand factor; BMI ⫽ body mass index; GP ⫽ glycoprotein.
Adapted from Michos et al.,318 with permission.
Statistically, approximately 3% of patients should be
expected to be hypo-responders based on their response
to arachidonic acid testing.89 The optimal management
of patients with a true lack of response to aspirin has not
been clarified.90 It is mandatory to ensure that reversible
causes of failure such as lack of compliance have been
addressed.35,91 Higher doses of aspirin may increase the
number of aspirin responders as determined by response
to in vitro tests of platelet function.92 This has been
observed clinically after cardiac surgery,93 and increased
aspirin doses have been associated with a reduction in
graft failure in the postoperative phase after cardiac
surgery.94 The use of alternative antiplatelet drugs such
as clopidogrel alone or in combination with aspirin
might be considered.95 However, the additional benefit
obtained has been modest when examined in randomized clinical trials.14 In addition, some patients with an
inadequate response to aspirin may also have an inadequate response to clopidogrel (i.e., dual “resistance”),
which may be particularly prevalent among women and
diabetics.96
The term “aspirin resistance” has also been used to
describe the inability of aspirin to protect individual
patients from thrombotic complications (often referred to
as clinical resistance).35,97–99 Without biochemical confirmation, the occurrence of a thrombotic event in a patient
while receiving aspirin therapy should more appropriately be labeled as a “treatment failure,” which may have
many causes other than the inability of aspirin to inhibit
TXA2 production (Table 3).100 Given the multiple pathways by which platelets are activated90 and by which
ischemic events can occur, it is unrealistic to expect any
single drug to abolish all ischemic events.101,102
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P2Y12 RECEPTOR BLOCKING DRUGS
The Thienopyridines
Clopidogrel
Efficacy
Originally introduced as a safer drug than its precursor
ticlopidine, clopidogrel has been shown to be marginally
more effective than aspirin for the secondary prevention
of vascular events.103 Given its cost and side-effect
profile, it should only be used as the primary drug for
the prevention of cardiovascular events in patients who
are intolerant or allergic to aspirin23 or to provide
enhanced protection when combined with aspirin23 (albeit with an increased risk of bleeding104). Treatment
should therefore be individualized based on guideline
recommendations.8 –12,15,23,31,32,105–107
Pharmacokinetics
Clopidogrel is a prodrug and has no direct antiplatelet
activity of its own. After oral administration of clopidogrel,
the drug is variably absorbed with approximately 50%
bioavailability.108 The majority of absorbed clopidogrel
(85%) is extensively hydrolyzed by esterases to the inactive
carboxylic acid metabolite SR 26334.109 In the liver, clopidogrel is metabolized in a 2-step process by CYP3A4/3A5
with additional contributions by CYP2B6/1A2/2C9/2C19110
to a very short-lived active metabolite (R130964), which is
responsible for its effect on platelet aggregation.111 This
process demonstrates considerable interpatient variability,112 and a genetic component to the variability is likely.85
Recent investigations have identified that variants of the
CYP2C19 genotype (e.g., the loss of function CYP2C19*2
allele113) are associated with diminished platelet response
to clopidogrel114,115 but this may be overcome by monitoring
ANESTHESIA & ANALGESIA
Antiplatelet Drugs in the Perioperative Period
Figure 3. A, Cytochrome P450 (CYP) 3A4 and CYP3A5 are major isoforms of the CYP3A system. Total CYP3A activity accounts for 20% of all
phase I reactions in the liver and metabolizes ⬎50% of drugs. Under usual conditions, in which both CYP3A4 and CYP3A5 contribute to total
CYP3A activity, CYP3A4 is probably the main contributor. Therefore, the antiplatelet activity of clopidogrel may not differ substantially between
patients with the CYP3A5 expressor genotype and those with the nonexpressor genotype. B, In the presence of multiple substrates or
inhibitors, CYP3A4 is more easily inhibited than CYP3A5, and therefore CYP3A5 becomes the main contributor to total CYP3A activity. In this
condition, total CYP3A activity would differ depending on the patient’s CYP3A5 genotype. (Photograph by Lianne Friesen and Nicholas
Woolridge.) (From Suh et al.,123 with permission.)
and adjusting the dose based on the platelet reactivity.116 Peak
concentrations of the parent drug, its active metabolite, and
the carboxylic acid metabolite occur within approximately 1
to 2 hours109,111 and there is little increased efficacy for doses
⬎600 mg because of limited drug absorption.117 The drug and
its metabolite are extensively bound to serum proteins. Elimination is by the feces (50%) and urine (50%).109 Dosage
adjustment is generally not necessary in patients with renal118
or hepatic119 dysfunction. Inhibition of platelet aggregation
reaches a level of approximately 40% to 60% after 3 to 7 days
of daily administration of 75 mg, but this time can be
significantly shortened by administering an initial loading
dose.120
Pharmacodynamics
Significant interpatient variability in antithrombotic effects
of clopidogrel has been ascribed to the variability in drug
absorption as well as to alterations and genetic differences
in hepatic metabolism.108,113–115,121 Clopidogrel’s active
metabolite binds to the platelet P2Y12 receptor to form
disulfide bridges with the extracellular cysteine residues
Cys17 and Cys270122 to irreversibly inhibit adenosine
diphosphate (ADP)-induced platelet aggregation.123 The
possibility of a rebound increase in platelet activity after
discontinuation of clopidogrel therapy has been raised by a
retrospective review demonstrating an increased incidence
of death and AMI clustered in the 90 days after discontinuation of clopidogrel.124 A subsequent prospective study could
not confirm these results although the number of patients
studied was small.125 Until this issue is further clarified, it is
suggested that care should be exercised when one is considering discontinuing clopidogrel before surgery.
Adverse Effects
The major side effect of clopidogrel administration is the
increased risk of bleeding.104 Use of clopidogrel in the
February 2011 • Volume 112 • Number 2
perioperative period has been associated with an increased
need for surgical reexploration for bleeding and use of
blood products after cardiac surgery.126 Use of a bleeding
management algorithm was associated with a reduction in
transfusion requirements after cardiac surgery in patients
treated with clopidogrel, although the bleeding rate was
still substantially higher than in a group of control patients
not receiving clopidogrel.127 A postoperative algorithm
based on reintroduction of antiplatelet drugs when chest
tube drainage was ⬍50 mL/h allowed the successful reintroduction of aspirin and clopidogrel without an increased
risk of bleeding.128 The side-effect profile of clopidogrel
necessitating early discontinuation because of side effects
includes neutropenia, thrombocytopenia, or hemorrhagic
events.129 Compared with aspirin, there were fewer GI symptoms but an increased incidence of diarrhea and rash. A rare
but significant complication of clopidogrel is the development
of thrombotic thrombocytopenic purpura.130
Drug Interactions
Because of the requirement for metabolism of clopidogrel
by CYP3A4/3A5 to generate the active metabolite, there is
the potential for clinically significant drug interactions,
which could lead to therapeutic failure.111,131 CYP3A represents 40% to 80% of the cytochromes responsible for drug
metabolism in humans,132 although there is substantial
variability. Clopidogrel is metabolized predominantly by
the 3A4 allele; however, 3A5 may contribute as much as
50% of hepatic CYP3A activity. The antiplatelet efficacy of
clopidogrel may be influenced by 3A5 functional polymorphism (Fig. 3).123 There is concern that drugs that are
CYP3A substrates (e.g., lipophilic statins) can inhibit the
metabolism of clopidogrel to its active metabolite and thus
lead to thrombosis.131 Most studies have not demonstrated
an increased risk for thrombosis in patients receiving both
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CYP3A4 metabolized statins and clopidogrel.133–136 However, there are significant limitations to the interpretation of
the results (reviewed in Neubauer and Mugge137), and
further study that accounts for confounders is required.
Clopidogrel activation to active metabolite is also dependent on metabolism by the CYP enzyme system.110
Randomized clinical trials have demonstrated the ability of
the PPIs to reduce the antiplatelet effect of clopidogrel138,139
and large observational studies have, in general, demonstrated that the combination may lead to an increased
mortality risk140,141 or readmission for MI.142 Given that
PPIs are recommended for patients receiving antiplatelet
drugs who have gastric irritation or bleeding,143 and because they are frequently prophylactically administered in
the perioperative period,144,145 patients receiving this combination of drugs should be monitored closely.
Clopidogrel HPR and Resistance
HPR also occurs with clopidogrel administration.61,146 As
with aspirin, the consequences of inadequate clopidogrel
effect on platelet reactivity can be devastating including
MI, stroke, and death,147 but in the absence of biochemical
testing (Fig. 2) to establish whether HPR exists, clinical
reports of clopidogrel “resistance”148,149 should more appropriately be considered treatment failures.
The response to clopidogrel administration also has a
bell-shaped curve and therefore a small percentage of
patients would statistically be described as poor responders
based on this phenomenon alone.112 Many of the same
factors leading to aspirin HPR apply also to clopidogrel
HPR (Table 3). Clopidogrel treatment factors for nonresponse that have been identified that are unrelated to
measurement of drug effect include noncompliance (the
incidence of which may far outweigh any degree of pharmacological HPR150), inability to pay for or access the
medication,151 and inadequate education about the necessity of continuing the medication at the time of hospital
discharge.152 Nevertheless, depending on the assay used, a
substantial proportion of patients (up to 31%153) who
receive clopidogrel in the usual doses are reported to have
an inadequate response in terms of antiplatelet activity154
and a significant proportion of these can have adverse
outcomes.60 Intrinsic factors that affect the interaction of
active metabolite with its receptors (such as genetic
alterations in the CYP2C19 gene, P2Y12 receptor polymorphisms, or alterations in intracellular signaling mechanisms) may also be involved (Table 3).155–157
However, some patients have been demonstrated to
have HPR in response to treatment with both aspirin and
clopidogrel.158 These patients seem to be at very high risk
for drug-eluting stent (DES) thrombosis or death.158 It
should be noted, however, that although dual antiplatelet
drug HPR may occur, HPR to one class of antiplatelet drugs
does not necessarily confer HPR to other classes of antiplatelet drugs. Some nonresponders to a 300-mg initial
loading dose of clopidogrel can be converted to responders
by increasing the loading dose,159 by increasing the maintenance dose,160 or by increasing both the loading and
maintenance dose.161 The degree of platelet reactivity (and
drug responsiveness) may differ depending on such things
as body mass index,116 stress,162 and the timing of drug
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administration in relation to the degree of platelet reactivity
during the inciting event such as PCI153 or surgery.163 Of
note, diabetic patients seem to have a consistently high
level of HPR when treated with thienopyridines.164 As with
aspirin, increased catecholamine levels have been identified as a risk factor for increased residual platelet reactivity
despite dual antiplatelet therapy.82,165 The perioperative
period may therefore be a period of increased risk for
thrombosis.166 Until this question has been studied, in
situations of high risk for thrombosis in which clopidogrel
was discontinued before surgery, it may be reasonable to
consider reinstitution of clopidogrel therapy with a bolus of
300 to 600 mg to reestablish adequate antiplatelet effects
after adequate hemostasis has been ensured.166 Antiplatelet
therapy should also include the use of aspirin,19 which
should be reinstituted as soon as hemostasis has been
achieved or on the morning after surgery.35
Prasugrel (CS-747, LY640315)
Prasugrel is one of several new drugs that also act at the
P2Y12 receptor167 (Fig. 1) and has been introduced into
practice for the prevention of thrombosis after PCI.33 It
belongs to the thienopyridine class of therapeutic drugs.168
Efficacy
Randomized clinical trials have established the efficacy of
prasugrel as an antithrombotic drug.169 In the setting of
PCI, initial studies suggested that prasugrel produced a
greater degree of platelet inhibition than clopidogrel and
was associated with fewer incidences of major adverse
cardiac events (MI, recurrent ischemia, and clinical target
vessel thrombosis).170,171 In a follow-up phase III study,
patients undergoing PCI and receiving aspirin were randomized to receive either prasugrel 60 mg as an initial
loading dose and then 10 mg daily (n ⫽ 6813) versus
clopidogrel 300 mg loading dose and 75 mg (n ⫽ 6795)
daily, and followed for 6 to 15 months.172 Prasugrel administration was associated with a significant reduction in
death from cardiovascular causes, nonfatal MI, or nonfatal
stroke (9.9% vs 12.1%). In addition, prasugrel produced a
significant reduction in the rates of MI (7.4% vs 9.7%),
urgent target vessel revascularization (2.5% vs 3.7%), and
stent thrombosis (1.1% vs 2.4%). However, there was an
increased risk of bleeding events, particularly in patients
older than 75 years of age, with a small body mass index,
with a history of stroke or transient ischemic attack (TIA),
and/or in those undergoing coronary artery bypass graft
(CABG) surgery. Subgroup analysis of patients receiving
coronary artery stents (either bare metal or DES) for ACS173
or ST segment elevation MI174 demonstrated improved
protection from in-stent thrombosis (and subsequent death
or MI) when prasugrel was given, without increased risk
for major bleeding complications. Other subgroup analyses
have shown greater protection using prasugrel in patients
with diabetes mellitus175 and a reduction in subsequent
thrombotic events after the initial event.176
Pharmacokinetics
Animal studies have shown prasugrel to be 10 to 100 times
more potent than clopidogrel in the inhibition of platelet
ANESTHESIA & ANALGESIA
Antiplatelet Drugs in the Perioperative Period
aggregation.168 Similar to clopidogrel, prasugrel is a prodrug and must be metabolized to an active metabolite to
exhibit its antiplatelet effect.177 Conversion of prasugrel to
its active metabolite is more rapid than clopidogrel, involving only a single cytochrome P450 – dependent step
(CYP3A4 and to a lesser extent CYP2B6),178 leading to
increased levels of the active metabolite and hence increased clinical effect.179 Prasugrel metabolism seems to be
less affected by genetic variations in CYP2C19 and CYP2C9
than clopidogrel180 and less affected by drug interactions
involving CYP3A4 for metabolism leading to less variation
in active metabolite formation.111 In healthy volunteers,
prasugrel is rapidly absorbed and metabolized after oral
administration with peak concentrations of the metabolites
occurring at 0.5 hour.181,182 Approximately 68% of a dose is
excreted as metabolites in the urine and the remainder in
the feces.181 Dose-finding studies have shown maximum
effects with an acceptable safety profile with an initial
loading dose of 40 to 60 mg, and dose-dependent inhibition
of platelet activity during maintenance dosing with a daily
dose of 15 mg producing a sustained response.183–185 The
ratio of the active metabolite for prasugrel has been reported to be 2.2 times higher than that for clopidogrel after
a loading dose, which may explain the faster onset of
activity, higher levels of active compound, and reduced
variability of platelet inhibition observed with prasugrel.179
Pharmacodynamics
In common with other thienopyridine derivatives, prasugrel’s active metabolite (R-138727) irreversibly binds to the
P2Y12 receptor by forming disulfide bridges between extracellular cysteine residues at positions Cys17 and Cys270 to
prevent platelet activation.122 In patients with stable coronary artery disease, prasugrel produced a faster and more
effective inhibition of platelet function than clopidogrel.186,187 In multiple-dose studies, the maximum antiplatelet effect occurred after 2 days and recovery of platelet
function occurred gradually over the 2 days after discontinuation of the drug.168 In a study comparing platelet
aggregation response to a loading dose of prasugrel 60 mg
or clopidogrel 300 mg, the incidence of poor platelet
aggregation response after prasugrel administration was
lower (0%) than for clopidogrel (17%– 43%).188 When
healthy subjects receiving clopidogrel therapy were
switched directly to prasugrel (with or without a loading
dose), greater inhibition of platelet aggregation was observed without an increased bleeding risk.189 In patients
with a demonstrated CYP2C19*2 loss of function allele with
reduced ability to generate the active metabolite of clopidogrel, use of prasugrel improved platelet function inhibition in patients for whom HPR was demonstrated using
clopidogrel.157
Adverse Effects
The major adverse effect of prasugrel is bleeding. Prasugrel
is a more potent inhibitor of platelet function than clopidogrel.190 In the phase III trial, prasugrel administration
was associated with a significantly increased incidence of
major adverse bleeding events (2.4% vs 1.8%; hazard ratio,
1.32).172 There was a higher incidence of life-threatening
bleeding (1.4% vs 0.9%), including nonfatal bleeding (1.1%
February 2011 • Volume 112 • Number 2
vs 0.9%) and fatal bleeding (0.4% vs 0.1%). Although it may
be anticipated that excess bleeding might occur based on
the increased potency of prasugrel, patients at risk for
bleeding were excluded from the trial to start, prompting
one editorialist to comment that more extended use of the
drug in excluded patients would likely be associated with
an even greater risk of bleeding.191 He calculated a
risk/benefit ratio of 1:1, i.e., for every additional life saved
by the use of prasugrel over clopidogrel, one could expect
an additional death due to bleeding. He noted in particular
that patients with a history of stroke or TIA were particularly susceptible to the adverse bleeding risk (2.3% vs 0%)
and suggested that, at the dose tested in this trial, prasugrel
should be avoided in patients with known cerebrovascular
disease. Subsequent analysis of bleeding events has determined that the majority occurred during the maintenance
phase of the study and might be ameliorated in high-risk
patients (age ⬎75 years or weight ⬍60 kg) by a reduction in
the maintenance dose.167,192
Drug Interactions
Because of the requirement for metabolism by the cytochrome
P450 system (CYP3A4/CYP2B6), there is a theoretical possibility of interactions with other drugs metabolized by that
system although enzyme kinetic studies suggest this is
unlikely.139,178,193
Prasugrel HPR
Compared with clopidogrel, use of prasugrel led to fewer
nonresponders and better clinical response in diabetic
patients.164 Poor response to clopidogrel (as measured by
light transmission aggregometry) was attributed to reductions in the amount of measured active metabolite available
to interact with platelets as opposed to alterations in the
platelet P2Y12 receptor.
The place of prasugrel in the management of atherothrombotic occlusive disease remains to be determined.
Further clinical trials are ongoing (e.g., TRILOGY-ACS,
SWAP, ACAPULCO, OPTIMUS-3), examining the potential utility of prasugrel in a variety of other patient populations.167 From a practical point of view, prasugrel is more
potent than clopidogrel but not shorter acting so one could
expect that in the perioperative period there may be an
increased risk of bleeding. When, or if, it should be discontinued in the perioperative period has not been studied but
discontinuance a minimum of 5 days before elective surgery
where there is significant risk of bleeding would be in keeping
with the guidelines suggested for clopidogrel and based on
the pharmacokinetic/pharmacodynamic properties of the
drug.168,183,184
Elinogrel (PRT060128)
Elinogrel is a direct-acting, reversible P2Y12 receptor inhibitor with a novel structure (sulfonylurea) and can be
administered both orally and IV.194 This allows for the
rapid onset of antiplatelet activity after IV administration
and then a transition to a predictable platelet inhibition
with the oral dosing form.195
Efficacy
Phase I studies demonstrated the ability to inhibit ADPinduced platelet aggregation within 20 minutes of administration; dose-dependent inhibition of platelet aggregation;
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synergism when administered with aspirin; and additional
inhibition of platelet aggregation in the Early Rapid Reversal of Platelet Thrombosis with IV Elinogrel before PCI to
Optimize Reperfusion in Acute Myocardial Infarction
(ERASE-MI) study. ERASE-MI was a phase IIA study in
subjects undergoing primary PCI and randomized to receive either elinogrel or placebo before the start of the
diagnostic angiogram that preceded the primary PCI procedure.196 It was conducted in 2 phases: phase I was a
dose-escalation study examining 10 mg (n ⫽ 10), or 20, 40,
or 60 mg (n ⫽ 20 each) or placebo; phase II was a
dose-confirmation study examining the highest tolerated
dose but was not completed because the sponsor terminated the study for administrative reasons. Patients could
receive aspirin, heparin, and clopidogrel but other anticoagulants were proscribed. No major bleeding events occurred in the treated population at any dose. No differences
in adverse events were recorded although they were numerically higher in the placebo group. The authors concluded that elinogrel, at the doses examined in this study,
was feasible and tolerable. The drug is undergoing further
study (INNOVATE PCI NCT00751231).
Pharmacokinetics and Pharmacodynamics
After administration of a 50-mg oral dose, approximately
56% of the total dose was excreted in urine and 48% in
feces. The main circulating compound was unchanged
elinogrel and the major compound excreted in urine and
feces was the parent compound. The major metabolic route
was by demethylation to form the metabolite PRT060301
(approximately 10%).194 In a study of 20 patients who had
previously undergone PCI and were being treated chronically with clopidogrel 75 mg and aspirin 81 mg daily and
screened for the presence of HPR, elinogrel 60 mg was
given orally between 12 and 16 hours after the previous
day’s dose of clopidogrel.197 The drug had a terminal
elimination half-life of 12 hours and was cleared by the
hepatic and renal routes with only limited metabolism.197
Peak concentration was observed at 4 to 6 hours followed
by a decrease to negligible levels by 24 hours. Plasma
concentrations mirrored the pharmacodynamic effect. The
antiplatelet effect peaked at 4 to 6 hours and returned to
predosing levels by 24 hours. In patients for whom HPR
was demonstrated while receiving aspirin and clopidogrel,
additional inhibition of platelet aggregation after elinogrel
administration occurred even in subjects known to have the
CYP2C19*2 allele.194
Adverse Effects
In the phase I clinical trials, single-dose elinogrel was well
tolerated with no serious or clinically significant adverse
events. In the phase IIa trial, the incidence of bleeding and
serious adverse events was similar.194 In theory, because of
its sulfonylurea backbone, patients with a history of adverse reactions to sulfonylurea drugs might be at increased
risk for development of allergic type reactions.
ADP RECEPTOR ANTAGONISTS
Cangrelor (AR-C69931)
Cangrelor is an ADP receptor antagonist that has been investigated in recent clinical trials167,198 (Fig. 1).33 Because it is a
300
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short-acting, IV, reversible inhibitor of platelet function, it has
the potential to play a significant role in the management of
patients with atherosclerotic disease in the perioperative period.
Efficacy
In small studies, cangrelor was an effective antithrombotic
drug in patients with ACS, unstable angina, or non–Q wave
MI.199,200 In a randomized clinical trial of patients with
AMI receiving cangrelor alone, alteplase alone, or 1 of 3
differing doses of cangrelor plus half-dose alteplase, cangrelor was an effective adjunct when added to alteplase for
resolution of ST segment elevation.201 The combination was
better than either drug alone. Researchers of 2 phase III
clinical trials using cangrelor in patients undergoing PCI
have recently reported their outcomes. Bhatt et al.202 performed a randomized trial of the addition of cangrelor or
placebo to clopidogrel in 5362 patients undergoing PCI
(CHAMPION PLATFORM Study). The primary end point
was a composite of death, MI, or ischemia-driven revascularization at 48 hours. There was no difference in the
primary end point between the 2 groups. In 2 prespecified
subgroup analyses, cangrelor produced a significant difference in the rate of stent thrombosis and death from any
cause. No differences in transfusion rate were observed
although a higher incidence of groin hematoma occurred in
the cangrelor-treated group. The trial was terminated early
when an interim analysis concluded that the trial was
unlikely to show superiority for the primary end point. The
second trial examined the effect of cangrelor or clopidogrel
administered to 8716 patients before undergoing PCI
(CHAMPION PCI Trial).203 The same composite end point
was used as in the CHAMPION PLATFORM trial. Again,
no difference in outcome was measured. This trial also was
terminated early for lack of efficacy.
Pharmacokinetics
Given IV, cangrelor has a rapid onset of action (steady state
at 30 minutes in the absence of a loading dose) and
clearance (50 L/h) with an elimination half-time of ⬍9
minutes. This leads to rapid return of platelet function
(within 60 minutes) when the drug is discontinued.204
Metabolism is by sequential dephosphorylation and there
are no active metabolites.167 The drug is metabolized in
plasma and metabolism seems to be independent of abnormalities of liver or kidney function suggesting its utility in
patients with impaired renal function.167
Pharmacodynamics
Cangrelor acts as a reversible inhibitor of the P2Y12 receptor on the platelet surface.205 It achieves greater inhibition
of platelet aggregation than that obtained by clopidogrel.206
Adverse Effects
In early clinical trials, cangrelor was well tolerated
(bleeding, transient increases in liver enzymes, and
bleeding at injection sites were the most common side
effects).199 –201,207 In patients undergoing PCI, cangrelor
was not associated with an increased bleeding risk in
patients receiving concomitant aspirin, heparin, and placebo for 18 to 24 hours, or, when compared with patients
receiving abciximab before PCI, with an increased risk of
bleeding or adverse cardiac events.207 In the phase III
ANESTHESIA & ANALGESIA
Antiplatelet Drugs in the Perioperative Period
clinical trials, cangrelor administration was associated with
trends toward increased bleeding.202,203 Although the
mechanism has not been determined, concern has been
raised about the possibility of an increased incidence of
dyspnea when drugs from this class are used.208
Drug Interactions
When given as combined therapy, cangrelor inhibited the
antiplatelet activity of clopidogrel but not when clopidogrel
was administered after cangrelor sequentially.209 The mechanism was postulated to be due to inhibition by cangrelor of
the binding of the active metabolite of clopidogrel to serine
residues of the P2Y12 receptor on the platelet surface.
An IV P2Y12 inhibitor might well serve as an effective
bridge to treatment in the perioperative period or in situations
whereby operative intervention is a possibility, and research
on the role cangrelor might have as bridge therapy for elective
cardiac surgery is continuing. Such a drug would be an
important advance in the safe management of patients requiring antiplatelet therapy in the perioperative period.
CYCLOPENTYLTRIAZOLOPYRIMIDINES
Ticagrelor (AZD6140)
Ticagrelor is an orally active reversible P2Y12 receptor
antagonist of the cyclopentyltriazolopyrimidine class of
drugs undergoing clinical trials167,210 (Fig. 1).33
Efficacy
Ticagrelor has been shown to rapidly and effectively inhibit
platelet aggregation at doses ranging from 50 to 200 mg
twice daily. On day 1, peak inhibition occurred at 2 to 4
hours whereas there was minimal inhibition demonstrated
with clopidogrel (75 mg twice a day). For the subset of 84
patients requiring CABG surgery in a phase II dose-finding
study of 2500 patients presenting with ACS,211 there was no
increased incidence of major bleeding in ticagrelor patients
requiring surgery within 24 hours of drug administration
overall (1 of 2 patients in the clopidogrel group versus 5 of
10 ticagrelor patients), but a tendency for reduced bleeding
for patients requiring surgery between days 1 and 5 was
observed. In the trial as a whole, there were more asymptomatic ventricular pauses observed in the ticagrelortreated patients. No differences in death occurred, but there
was a slight trend toward reduced incidence of MI in
ticagrelor-treated patients.
Ticagrelor was subsequently evaluated in a phase III,
double-blind, randomized clinical trial (Study of Platelet
Inhibition and patient Outcomes [PLATO]) in patients with
ACS.212 Patients with ACS, with or without ST segment
elevation, were randomized to receive ticagrelor 180-mg
loading dose followed by 90 mg twice daily (n ⫽ 9333) or
clopidogrel 300- to 600-mg loading dose followed by 75 mg
daily (n ⫽ 9291) for the prevention of cardiovascular
events. The primary end point (a composite end point of
time to the earliest occurrence of MI, stroke, or death from
vascular causes) occurred in significantly fewer patients
when examined at the 12-month follow-up time point
(ticagrelor 9.8% vs clopidogrel 11.7%; P ⬍ 0.001). For
patients receiving a stent, the rate of stent thrombosis was
significantly lower in the ticagrelor group (1.3% vs 1.9%;
P ⫽ 0.009). No differences in the rate of major bleeding
February 2011 • Volume 112 • Number 2
complications were observed (ticagrelor 11.6% vs clopidogrel 11.2%; P ⫽ 0.43). Analysis of the stroke subpopulation alone revealed an increased incidence of hemorrhagic
stroke (0.2% vs 0.1%; P ⫽ 0.10). In the subpopulation of
patients undergoing CABG surgery, no difference in the
rate of major bleeding complications was observed (ticagrelor 7.4% [n ⫽ 619] vs clopidogrel 7.9% [n ⫽ 654]). An
increased incidence of major or minor bleeding (16.1% vs
14.6%; P ⫽ 0.008), dyspnea requiring discontinuation of
treatment (0.9% vs 0.1%; P ⬍ 0.001), ventricular pauses of
⬎3 seconds within the first week of therapy (5.8% vs 3.6%;
P ⫽ 0.01), and discontinuation as a result of any adverse
event (7.4% vs 6.0%; P ⬍ 0.001) was observed in the study
population as a whole. The authors concluded that ticagrelor was more effective than clopidogrel for the management of patients with ACS without an increased bleeding
risk. An accompanying editorial suggested that, because of
its reversible effect on platelet function, ticagrelor may have
utility in patients for whom the coronary anatomy is
unknown and in whom a CABG procedure is deemed
probable.213 In addition, for patients receiving prasugrel or
clopidogrel and requiring elective surgery, switching them
to ticagrelor 5 to 7 days before surgery could be considered.
Caution with its use in patients with a history of stroke or
TIA was advised. These recommendations require verification in properly conducted clinical trials. In a predefined
subset of patients undergoing a planned invasive strategy,
fewer patients randomized to the ticagrelor group had the
composite outcome of cardiovascular death, MI, or stroke
without an increased incidence of bleeding compared with
the group randomized to clopidogrel treatment.214 In a
randomized, crossover study, use of ticagrelor produced
increased platelet inhibition as compared with clopidogrel
and more patients considered nonresponsive to clopidogrel215 became responsive to ticagrelor than vice versa.
Pharmacokinetics
Ticagrelor is absorbed orally and does not require metabolic activation for its clinical effect.216,217 It has one known
active metabolite, which is present in blood at a concentration approximately one-third that of the parent compound
as determined in phase I trials.216,217 After oral dosing in
healthy volunteers, peak effect on platelet inhibition was
measured at 2 to 4 hours.216 The drug seems to have linear
kinetics217 and after twice-daily administration of ticagrelor
to patients with atherosclerotic disease, there was a linear
and dose-related increase in ticagrelor and its active metabolite with no age- or gender-related differences.216 The
terminal half-life was approximately 7 hours.217
Pharmacodynamics
Ticagrelor binds to the P2Y12 receptor in a reversible
manner and nearly completely inhibits ADP-induced platelet aggregation.216,218 It has a faster onset and offset of
platelet inhibition than clopidogrel.219 Ticagrelor has been
shown to rapidly and effectively inhibit platelet aggregation at doses ranging from 50 to 200 mg twice daily.216 Its
ability to interact with the P2Y12 receptor does not seem to
be affected by alterations in single nucleotide polymorphisms of the receptor gene.220 Ticagrelor produces more
rapid and greater inhibition of platelet aggregation than
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REVIEW ARTICLE
clopidogrel.216,221 Doses ⬎100 mg produced very little
additional increase in the degree of inhibition of platelet
aggregation. When compared with clopidogrel, no differences in inflammatory markers measured in a group of
patients with ACS were detected.222
glycoprotein,230 with consequent reduction in drug effect.231
Because ␣1-acid glycoprotein is an acute phase reactant whose
levels increase in the perioperative period,232 there is a possibility of reduced drug effect because of increased protein
binding if dosing is not increased.
Adverse Effects
The most common adverse event after ticagrelor administration was bleeding.216 Dyspnea requiring discontinuation
of therapy occurred in a larger proportion of patients (0.9%
ticagrelor vs 0.1% clopidogrel) in the PLATO trial.212 In the
ONSET/OFFSET study comparing ticagrelor (n ⫽ 57),
clopidogrel (n ⫽ 54), or placebo (n ⫽ 12),219 in patients with
stable coronary artery disease, the incidence of dyspnea
and effect on pulmonary function measured by pulmonary
function studies were examined.223 The incidence of dyspnea was 38.6% in ticagrelor-treated patients, 9.3% in the
clopidogrel group, and 8.3% in the placebo group (P ⬍
0.001). Dyspnea led to drug discontinuation in 3 patients in
the ticagrelor group and was reversible. Dyspnea occurred
early (within the first week) in the majority of affected
patients and was described as mild. No changes in pulmonary function in any group were measured. Dyspnea was
not a function of altered pharmacokinetic parameters.
Pharmacodynamics
The mechanism of action is thought to be via increased cyclic
adenosine monophosphate (cAMP) by inhibition of nucleotide phosphodiesterase, blockade of the uptake of adenosine
thereby increasing the amount of adenosine at the platelet
vascular interface,227 or direct stimulation of prostacyclin
release from the endothelium.227 In high doses, drug-induced
vasodilation and tachycardia may produce myocardial ischemia, which may be a limiting factor for its use as an
antiplatelet drug.233 Compared with aspirin or clopidogrel,
dipyridamole produced sustained platelet inhibition but via a
broader range of mechanisms.234,235
PHOSPHODIESTERASE INHIBITORS
Dipyridamole
Dipyridamole is a pyrimidopyrimidine derivative with
vasodilator and antiplatelet properties.224
Efficacy
Previous studies using the immediate-release formulation of
dipyridamole did not, in general, show it to be superior to
other antiplatelet drugs, and its side-effect profile (mainly
headache) limited its application.225 However, more recent
guidelines now include aspirin and extended-release dipyridamole as an acceptable choice for the prevention of cerebral
ischemic events in patients with noncardioembolic TIA or
stroke.3,4,105 Dipyridamole is inferior to clopidogrel treatment
for aspirin-intolerant patients undergoing PCI and is not
recommended for patients undergoing CABG surgery.3 Aspirin continues to be the first choice for prevention of occlusive vascular disease followed by clopidogrel and cilostazol
for certain populations.3
However, given the above recommendations and in
particular for stroke management, it is likely that anesthesiologists will encounter patients receiving the combined
therapy, i.e., aspirin and extended-release dipyridamole.
Perioperative management should weigh the risks and
benefits including the possibility of increased risk of bleeding caused by the combination.
Pharmacokinetics
Absorption of oral doses of dipyridamole is quite variable226,227 but a modified-release formulation has improved the bioavailability.228 The drug is metabolized to a
glucuronide, excreted primarily in bile, and subject to
enterohepatic recirculation with a terminal half-life of 19
hours making twice-daily dosage possible particularly
when the modified-release formulation is used.229 Dipyridamole is highly protein bound to albumin and ␣1-acid
302
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Adverse Effects
Use of dipyridamole is associated with an increased risk of
bleeding events.47 The most common adverse effect of
chronic administration is headache.236 Dipyridamole has
been used for cardiac diagnostic testing including stress
echocardiograms (single-dose studies) and in that population there is a small incidence of death (0.9:10,000), stroke
or TIA (1.22:10,000), AMI (1.76:10,000), bronchospasm
(1.22:10,000), and arrhythmias (0.81:10,000) detected.237
Drug Interactions
When coadministered with aspirin, there is an increased
risk for bleeding.47 Although we could find no substantiating reports, it is possible that there could be additive
hypotensive effects if dipyridamole was administered with
other drugs that are vasodilators, e.g., ACE inhibitors.
Cilostazol
Cilostazol is a phosphodiesterase 3 inhibitor with vasodilator and antiplatelet aggregation properties238 (Fig. 1).33
Efficacy
Cilostazol has been demonstrated to be effective in the
setting of peripheral vascular disease239 and is currently
recommended for patients with moderate-to-severe disabling intermittent claudication who do not respond to
exercise therapy, and who are not candidates for surgical or
catheter-based interventions.31 Cilostazol has been shown
to prevent stent thrombosis and restenosis.240,241 An enhanced antiplatelet effect of triple therapy (with aspirin and
clopidogrel) has been demonstrated,242 although side effects with cilostazol (skin rash and GI upset) limited its
use.243,244 For the prevention of stroke, Gotoh et al.245
demonstrated a significant reduction in recurrence of cerebral
infarction as compared with placebo alone. In a randomized
trial examining the relative merits of cilostazol versus aspirin
in patients with an ischemic stroke using as the primary
outcome the recurrence of stroke, Huang et al.246 determined
that there was no difference in the ischemic stroke reoccurrence rate but patients treated with cilostazol had lower rates
of cerebral bleeding suggesting perhaps an improved safety
profile. Compared with aspirin alone, cilostazol and aspirin
ANESTHESIA & ANALGESIA
Antiplatelet Drugs in the Perioperative Period
demonstrated enhanced antiplatelet activity in patients undergoing off-pump coronary artery surgery.247
Pharmacokinetics
There is large variability in the absorption of orally administered cilostazol248 that does not seem to be attributable to
the activity of the drug transporter P-glycoprotein.249 The
drug is metabolized primarily by CYP3A4/5 with a lesser
contribution by CYP2C19 to inactive metabolites.250 It is
extensively protein bound (approximately 95% primarily to
albumin).251 The elimination half-time for cilostazol is
approximately 10 hours.252 No differences in pharmacokinetics were detected based on age or gender in healthy
subjects aged 50 to 80 years.251,252 Although the clearance
of cilostazol was increased in patients with renal failure253
and decreased in patients with liver failure,252,254 no dosage adjustments were necessary.
Pharmacodynamics
Cilostazol is a more potent inhibitor of platelet aggregation
than ticlopidine or aspirin.255 Its mechanism of action is to
inhibit the intracellular enzyme phosphodiesterase 3 leading to an increase in cyclic adenosine monophosphate with
resultant decreases in platelet aggregation and vasodilation.252 Similar concerns about producing hypotension and
tachycardia as a result of vasodilation as are present with
dipyridamole are also relevant here.256
Adverse Effects
Headache is a common side effect of treatment with cilostazol
and may be a reason some patients discontinue therapy.257 In
a postregistration placebo-controlled, randomized, doubleblind safety trial of the use of cilostazol in patients with
peripheral vascular disease, a significant proportion of patients discontinued therapy (60%).258 There was no increased
incidence of death or bleeding. A blinded post hoc analysis
demonstrated an increased risk of cerebral vascular events in
patients in the placebo arm (6.1% vs 3.2%).259
Drug Interactions
Because of its metabolism by CYP3A4 and CYP2C19, cilostazol may be involved in drug interactions with drugs also
requiring these isoforms for their metabolism. Cilostazol
metabolism was inhibited by omeprazole (a CYP2C19 inhibitor) and erythromycin (a potent inhibitor of CYP3A4) with
resultant decreases in plasma concentrations of cilostazol and
its active metabolite.260,261 Coadministration with lovastatin
(a CYP3A4 substrate) resulted in reductions in cilostazol plasma
concentrations but not to clinically significant levels.262 Lovastatin levels were increased but not to levels requiring dosage
adjustments. There were no reports of a clinically significant
interaction when coadministered with aspirin.252
PERIOPERATIVE MANAGEMENT
Antiplatelet drugs may increase the risk of surgical bleeding. However, there have been several reports of stent
thrombosis and death in the perioperative period when
antiplatelet drugs were discontinued.34 In addition, increased mortality when surgery is delayed in patients
taking antiplatelet drugs to allow coagulation variables to
normalize has been reported.263 These reports have raised
concern about the appropriate management of antiplatelet
February 2011 • Volume 112 • Number 2
drugs in the perioperative period.264 The most appropriate
timing of surgery after insertion of a bare metal stent or
DES is still under active investigation but initial reports
suggest that surgery within the first 3 months after insertion of either type of stent is particularly hazardous.34,265
Thereafter, problems with late stent thrombosis are more
prevalent in patients receiving DESs.266 Although there
seems to be no time frame when the risk becomes zero
regardless of when a DES was inserted,267 recent data
suggest that the benefit of continuing dual antiplatelet
therapy beyond 12 months is marginal.268
As a consequence of these concerns, the American Heart
Association has released a statement13 concerning premature discontinuation of dual antiplatelet therapy in patients
with coronary artery stents. This advisory comments that
stent thrombosis is a catastrophic event with the incidence
of death between 20% and 45% or MI up to 64%. It may be
more common than previously appreciated particularly
because there is increasing usage of these stents in patients
with more complicated disease than those who were originally studied (so-called “off label” usage).269 Although
there were few data upon which to make any recommendation, the American Heart Association advisory observed
that the objective evidence for an increased risk of
bleeding during noncardiac surgery in patients with dual
antiplatelet therapy continued perioperatively was weak.
However, a recent report suggests that as many as 26% of
patients will require noncardiac surgery within 5 years
after PCI and, of these, 8.6% will have a bleeding
episode.270 These data suggest that as the use of antiplatelet therapy after DES continues and more patients
receiving them present for elective surgery, there will be
an increased risk for adverse bleeding outcomes in this
population. The general experience with cardiac surgery is
that there are increased bleeding complications when
clopidogrel is part of dual antiplatelet therapy that is
continued into the perioperative period.17,18,271,272 Where
possible, aspirin should be continued throughout the perioperative period. The advisory panel could find no satisfactory “bridge” therapy for stent patients during this
period because anticoagulants had been determined to be
unsatisfactory in this regard and led to increased bleeding.
There were no data supporting the efficacy of glycoprotein
IIb/IIIa drugs in this situation. They suggested that, in
keeping with the advice given by a recent Food and Drug
Administration panela for all patients receiving DES, dual
antiplatelet therapy should be continued for 12 months
after stent insertion. (Support for this recommendation has
been provided in a study that demonstrated that clopidogrel use for ⬎1 year was associated with a lower
mortality in patients having PCI and stent placement.273)
The panel also made additional recommendations concerning the management of patients receiving a DES. These
were as follows:
1. “Before implantation of a stent, the physician should
discuss the need for dual antiplatelet therapy. In
patients not expected to comply with 12 months of
a
United States Food and Drug Administration Circulatory System Devices
Panel. Available at: http://www.fda.gov/ohrms/dockets/ac/cdrh06.
html#circulatory. Last accessed November 19, 2010.
www.anesthesia-analgesia.org
303
REVIEW ARTICLE
2.
3.
4.
5.
6.
7.
8.
thienopyridine therapy, whether for economic or
other reasons, strong consideration should be given
to avoiding a drug-eluting stent (DES).
In patients who are undergoing preparation for percutaneous coronary intervention and are likely to
require invasive or surgical procedures within 12
months, consideration should be given to implantation of a bare-metal stent or performance of balloon
angioplasty with provisional stent implantation instead of the routine use of DES.
A greater effort by healthcare professionals must be
made before patient discharge to ensure patients are
properly and thoroughly educated about the reasons
they are prescribed thienopyridines and the significant
risks associated with prematurely discontinuing such
therapy.
Patients should be specifically instructed before hospital discharge to contact their treating cardiologist before
stopping any antiplatelet therapy, even if instructed to
stop such therapy by another healthcare provider.
Healthcare providers who perform invasive or surgical procedures and are concerned about periprocedural and postprocedural bleeding must be made
aware of the potentially catastrophic risks of premature discontinuation of thienopyridine therapy. Such
professionals who perform these procedures should
contact the patient’s cardiologist if issues regarding
the patient’s antiplatelet therapy are unclear to discuss optimal patient management strategy.
Elective procedures for which there is significant risk of
perioperative or postoperative bleeding should be deferred until patients have completed an appropriate
course of thienopyridine therapy (12 months after DES
implantation if they are not at high risk of bleeding and a
minimum of 1 month for bare-metal stent implantation).
For patients treated with DES who are to undergo
subsequent procedures that mandate discontinuation
of thienopyridine therapy, aspirin should be continued if at all possible and the thienopyridine restarted
as soon as possible after the procedure because of
concerns about late-stent thrombosis.
The healthcare industry, insurers, the US Congress,
and the pharmaceutical industry should ensure that
issues such as drug cost do not cause patients to
prematurely discontinue thienopyridine therapy and to
thus incur catastrophic cardiovascular complications.”
Clearly, these recommendations have significant implications for anesthesiologists who manage patients during the
perioperative period and will require appropriate consultation with surgeons and cardiologists as well as a clear
understanding of the risk-benefit ratio for performance of
procedures such as regional blocks, epidurals, and spinals.274 Given that all new antiplatelet drugs will be
required to be at least as effective as clopidogrel and the
current recommendations against the performance of regional anesthesia when clopidogrel is present,275 we suggest that, where possible, regional anesthesia should only
be performed when it is certain that the return of adequate
platelet function has been ascertained (Table 1). Although
their value as monitors of drug effect continues to
304
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evolve,276 –279 this may be a place for the use of platelet
function monitors in the perioperative period. Catheters
placed perioperatively should be removed before reinstitution of antiplatelet therapy.
The Society for Cardiovascular Angiography and Interventions Drug-eluting Stent Task Force have also released
their recommendations.280 They provide “practical advice”
on a number of related issues such as patient selection,
stent implantation, and medical-legal concerns. Of most
relevance to anesthesiologists is the section on dual antiplatelet therapy. They concur with the Food and Drug
Administration panel recommendation to increase the duration of dual antiplatelet therapy to 12 months from 3
months for patients receiving DESs. Furthermore, despite a
lack of conclusive evidence, they suggest that patients in
whom stent thrombosis may be catastrophic or lethal
should undergo platelet aggregation studies and where
appropriate, the dose of clopidogrel should be increased to
150 mg/d when platelet aggregation studies show ⬍50%
inhibition (a study in patients with type 2 diabetes mellitus
lends some strength to this recommendation281). They
found no evidence that patients who have completed or
discontinued their course of dual antiplatelet therapy,
without incident, should restart thienopyridine therapy,
although they should continue taking aspirin indefinitely.
They reiterated that there are no proven “bridging” therapies for patients who must discontinue dual antiplatelet
therapy for surgery.
Recognizing that cardiac surgery is associated with
generation of an inflammatory response leading to increased platelet activation81,83 and turnover86 with resultant HPR for both aspirin and clopidogrel,20,88,166 the
following approaches should be considered:
• Aspirin therapy should be continued preoperatively
and throughout the perioperative period26 unless the
risk of bleeding is considered to be high or the
consequences of bleeding are significant, e.g., ophthalmological surgery.35
• Although there are currently no satisfactory risk
stratification schemes with respect to the management
of bleeding risk in patients taking antiplatelet drugs in
the perioperative period,282 patients undergoing urological surgery, major vascular surgery, cardiac surgery with identified risk factors,283 neurosurgery
involving the brain or spinal cord, or where the
complications of bleeding might be catastrophic, e.g.,
ophthalmic surgery, clopidogrel should be discontinued 5 days preoperatively.10,19
• In patients at high risk of thrombotic complications
(e.g., those with a DES in place), use of a higher dose
of aspirin (e.g., 325 mg) in the postoperative period
should be considered19,94 with a return to a dose of 81
mg daily after 30 days.88Using a variety of tests of
platelet function, Golański et al.88 demonstrated that
37.5% of patients receiving 325 mg of aspirin after
cardiac surgery were responders at day 10 postoperatively, increasing to a 96% response rate at 30 days,
which forms the basis for this recommendation. In the
postoperative period for patients at high risk of
thrombotic complications (e.g., those with a DES in
ANESTHESIA & ANALGESIA
February 2011 • Volume 112 • Number 2
Dunning et al.19
Refs. 8, 10, 13,
and 106
European Association
of Cardiothoracic
Surgery
American College
of Cardiology/
American Heart
Association
American College
of Chest
Physicians
Reference
document
Douketis et al.282
In DES patients who must undergo For ACS/NSTEMI patients for
CABG as a postangiography
urgent surgery that mandates
management strategy:
discontinuation of thienopyridine
discontinue clopidogrel 5–7 d
therapy, it is reasonable to
before elective CABG.8,10
continue aspirin if at all possible
Elective procedures for which
and restart thienopyridine as
there is significant risk of
soon as possible.13,106 Elective
noncardiac surgery is not
perioperative or postoperative
recommended within 4–6 wk of
bleeding should be deferred
bare-metal coronary stent
until patients have completed
implantation in patients in whom
an appropriate course of
thienopyridine or aspirin and
thienopyridine therapy (12 mo
thienopyridine therapy will need
after DES implantation and a
to be discontinued
minimum of 1 mo for BMS
perioperatively.106 For ACS/
implantation)13
NSTEMI patients for CABG,
continue aspirin10
Aspirin recommendation
Clopidogrel recommendation
Aspirin recommendation
for
for
for
postoperative management
preoperative management
preoperative management
Stop 7–10 d for patients not at
Stop 7–10 d for patients not at Start 24 h postoperatively for
high risk for cardiac events. For
high risk for cardiac events.
patients not at high risk
elective CABG or high-risk
For elective CABG or high-risk
for cardiac events (or the
noncardiac surgery patients
noncardiac surgery patients
next morning) when
(exclusive of coronary stents),
(exclusive of coronary stents),
adequate hemostasis has
continue aspirin up to and
stop clopidogrel at least 5 d,
been achieved. For
beyond the time of surgery. If
and preferably, within 10 d of
patients at high risk for
aspirin is interrupted, it should
surgery. In BMS patients
cardiac event, or
be restarted 6–48 h after CABG.
within 6 wk of stent
undergoing CABG, or with
In BMS patients within 6 wk of
placement, or DES patients
stent placement, continue
stent placement, or DES
within 12 mo of stent
throughout perioperative
patients within 12 mo of stent
placement, continue
period (see preoperative
placement, continue aspirin in
clopidogrel in the
recommendations). No
the perioperative period
perioperative period
dosing recommendation
Stop 2–10 d for elective cardiac
Stop 5–7 d for urgent cardiac
Start 150–325 mg (325 mg
surgery. For ACS, continue until
surgery
preferred) within 24 h
day of surgery
(preferably within 6 h) of
cardiac surgery and
continued for 1 y
(Continued)
Routine use of
Clopidogrel recommendation
platelet function
for postoperative
monitoring
management
Start 24 h postoperatively for No
patients not at high risk
for cardiac events (or the
next morning) when
adequate hemostasis has
been achieved. For
patients at high risk for
cardiac event, or
undergoing CABG, or with
stent placement, continue
throughout perioperative
period (see preoperative
recommendations). No
dosing recommendation
Start clopidogrel 75 mg
Thromboelastography
acceptable alternative to
aspirin for graft patency.
For patients having CABG
for ACS, clopidogrel
administration for 9–12
mo should be considered.
For patients having cardiac
surgery with a stent in
situ, clopidogrel should be
continued if the stented
vessel has not been grafted
Recommence as soon as
Recommence as soon as
None given
possible. For patients with
possible. For patients with
DES, consider dual therapy
DES, consider dual therapy
for 1 y
for 1 y
Table 4. Comparison of Guideline Recommendations Regarding Antiplatelet Therapy in the Perioperative Period
Antiplatelet Drugs in the Perioperative Period
www.anesthesia-analgesia.org
305
306
www.anesthesia-analgesia.org
BMS ⫽ bare metal stent; DES ⫽ drug-eluting stent; ACS ⫽ acute coronary syndrome; NSTEMI ⫽ non-ST-segment elevation myocardial infarction; CABG ⫽ coronary artery bypass graft.
Reference
document
Present article
Table 4. (Continued)
Aspirin recommendation
for
preoperative management
Assess risk of bleeding. Continue
throughout perioperative period
if possible
Clopidogrel recommendation
for
preoperative management
Assess risk of bleeding. If
necessary, discontinue 5 d
preoperatively
Routine use of
Clopidogrel recommendation
Aspirin recommendation
platelet function
for postoperative
for
monitoring
management
postoperative management
Assess thrombotic risk. If
Assess thrombotic risk. If
Perhaps in certain
high and aspirin
high and clopidogrel
clinical situations
discontinued
discontinued
such as to assess
preoperatively, initiate
preoperatively, give 1
compliance and
aspirin 325 mg daily for
initial postoperative dose
timing of drug
30 d then step down to 81
of 300–600 mg and
initiation
mg daily
reinitiate maintenance
therapy at 150 mg daily for
30 d then step down to 75
mg daily
REVIEW ARTICLE
place) receiving clopidogrel, when the drug has been
discontinued for ⱖ5 days in the perioperative period
and there are no signs of ongoing bleeding, consideration should be given to rebolusing the drug (300 – 600
mg) with use of a higher maintenance dose (150 mg)
for 30 days.166,284
• Resumption and continuation of other standard medical therapies including ACE inhibitors, statins,
␤-blockers, etc., should be initiated as soon as possible
in the postoperative period.285
It should be recognized that these suggestions differ
slightly from recently released guidelines primarily by
suggesting clopidogrel discontinuation at 5 days before
surgery (as opposed to 7–10 days),282,286and the use of
rebolusing and higher maintenance doses postoperatively19,35,282 (Table 4). There is a lack of uniformity in
the guideline recommendations (e.g., when [or if] aspirin
should be discontinued preoperatively, when clopidogrel should be discontinued preoperatively, when
aspirin therapy should be reinitiated postoperatively and
at what dose, when clopidogrel therapy should be reinitiated and at what dose, the duration of antiplatelet
therapy postoperatively, and the role of platelet function
monitors19,282), no doubt a reflection of the rapidly
advancing knowledge base upon which recommendations can be made.
Bleeding: Prevention and Management
of Complications
Although the degree to which antiplatelet therapy continuation contributes to transfusion requirements intraoperatively is uncertain,287,288 it has to be acknowledged
that continuing antiplatelet therapy in the perioperative
period is not without risk for bleeding complications,17,26,271,289 including after performance of regional
anesthesia,290,291 suggesting that an individualized approach to management of antiplatelet therapy is prudent.
Guidelines on the management of antiplatelet therapy
before cardiac surgery have been published.19,292 Continued use of clopidogrel may lead to more blood
product usage and need for surgical reexploration,19
each of which carries additional risk for the patient.293–296 Similarly, continued use of aspirin may lead
to increased risk for transfusion and surgical reexploration.19 Use of point-of-care platelet function monitors or
standard platelet aggregometry may allow one to determine the degree of residual drug effect and therefore the
ability to make an informed decision about the safety of
performing regional anesthesia. The merits of each platelet function test to measure drug effect on platelet activity
have been reviewed elsewhere and will not be further
considered here.297 If the performance of regional anesthesia is considered essential, platelet administration could be
guided by platelet function monitoring if available.298
Other potential perioperative uses of platelet function
monitoring include evaluation of patient compliance, timing of surgery, identification of “hyper-responders” for
whom continuation of aspirin or clopidogrel in the perioperative period might lead to an increased risk of bleeding,
and as part of a transfusion algorithm to guide blood
component administration.64,127,299 –302
ANESTHESIA & ANALGESIA
Antiplatelet Drugs in the Perioperative Period
Figure 4. Flow chart to determine the risk
of stent thrombosis. N.B. It is also essential to determine the level of compliance
with antiplatelet medication administration
when assessing risk. (From Riddell et
al.,316 with permission.)
As regards the intraoperative management, in addition to component blood therapy including platelets, a
meta-analysis has determined that the combined use of
aspirin and antifibrinolytics did not increase prothrombotic complications and suggests that antifibrinolytics
may reduce bleeding complications and have a role in
the management of bleeding risk in high-risk patients
receiving antiplatelet drugs perioperatively.303 The merits of which antifibrinolytic drug is best given their risk
and benefits continue to be debated304 –307 and are beyond the scope of this review. There may be merit in
using point-of-care devices to reduce transfusion requirements and guide component therapy.308 –312 When
hemorrhage is severe and unresponsive to conventional
treatment, recombinant activated factor VII may be considered, although the possibility of increased thrombotic
complications must also be considered, especially in
patients with vascular disease.19,313–315
An Approach to Management
To help determine the best approach to the management
of patients in the perioperative period, Riddell et al. have
February 2011 • Volume 112 • Number 2
provided some advice based on consensus opinion.316
The first step is to determine the risk of bleeding (not
only the quantity but also the site, e.g., ophthalmological
surgery) in consultation with the surgeon and cardiologist. The next step is to determine the risk of stent
thrombosis (Fig. 4).316 Finally, by assessing both risks,
recommendations as to what to do with oral antiplatelet
drugs are provided (Table 5).316
CONCLUSIONS
We have reviewed some of the issues of concern regarding
the use of antiplatelet drugs in the perioperative period. In
general, the safest approach to prevent thrombosis seems to
be continuation of these drugs throughout the perioperative period except when concerns about perioperative
bleeding outweigh those associated with the development
of thrombotic occlusion. In situations in which a large
inflammatory response is expected, higher doses or use of
dual antiplatelet therapy may be indicated. Aspirin and
clopidogrel (alone and in combination) have been the
most studied and have the best-known risk-benefit profiles of drugs currently available. Other drugs, e.g.,
www.anesthesia-analgesia.org
307
REVIEW ARTICLE
Table 5. Assessing the Risk of Surgery and Possible Stent Thrombosis
Risk of stent
thrombosis
High
Moderate
Low
Risk of surgical bleeding
High
Stop all OADs
Consider short-acting IV antiplatelet drugs
while off OADs
Proceed with surgery
Restart OADs as soon as possible after
surgery
Stop all OADs
Proceed with surgery
Restart OADs as soon as possible after
surgery
Stop all OADs
Proceed with surgery
Restart OADs as soon as possible after
surgery
Moderate
Continue at least 1 OAD if possible
Consider short-acting IV antiplatelet agents
while off OADs
Proceed with surgery
Restart OADs as soon as possible after
surgery
Continue 1 OAD if possible
Proceed with surgery
Restart OADs as soon as possible after
surgery
Stop all OADs
Proceed with surgery
Restart OADs as soon as possible after
surgery
Low
Continue all OADs
Proceed with surgery
Continue all OADs
Proceed with surgery
Continue 1 OAD if possible
Proceed with surgery
Restart OADs as soon as possible
after surgery
OAD ⫽ oral antiplatelet drug.
N.B. Where possible, compliance should be checked and appropriate platelet function tests performed.
Modified from Riddell et al.,316 with permission.
prasugrel, dipyridamole, and cilostazol, have not been as
extensively investigated. Whether drugs such as cangrelor and ticagrelor confer additional benefits remains to
be established. Knowledge of the pharmacodynamics
and pharmacokinetics may allow practitioners to anticipate difficulties associated with drug withdrawal and
administration in the perioperative period including the
potential for drug interactions.
DISCLOSURES
Name: Richard Hall, MD, FRCPC, FCCP
Conflicts of Interest: Dr. Hall has previously received honoraria from Bayer, Eisai, and Eli Lilly (makers of pharmaceutical
agents referred to in this article).
Name: C. David Mazer, MD, FRCPC
Conflicts of Interest: Dr. Mazer has previously received honoraria from Bayer, AstraZeneca, and Bristol-Myers Squibb
(makers of pharmaceutical agents referred to in this article).
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